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I. Smith



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    MO18 - NSCLC - Targeted Therapies IV (ID 116)

    • Event: WCLC 2013
    • Type: Mini Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      MO18.12 - Impact of <em>KRAS</em> codon sub-types in a Phase II second-line trial in <em>KRAS</em>-mutant advanced non-small cell lung cancer (NSCLC) of selumetinib plus docetaxel versus docetaxel alone (ID 3331)

      16:15 - 17:45  |  Author(s): I. Smith

      • Abstract
      • Presentation
      • Slides

      Background
      Phase II data from patients with KRAS mutation-positive NSCLC, selumetinib (AZD6244, ARRY-142886) plus docetaxel showed promising efficacy versus placebo plus docetaxel alone (Jänne et al. Lancet Oncol 2013;14:38–47). Median OS was 9.4 months (95% CI 6.8–13.6) in the selumetinib group and 5.2 months (95% CI 3.8–non-calculable) in the placebo group (HR for death 0∙80, 80% CI 0.56–1.14; one-sided p=0.21). Median PFS was 5.3 months (95% CI 4.6–6.4) and 2.1 months (95% CI 1.4–3.7), respectively (HR for progression 0∙58, 80% CI 0.42–0.79; one-sided p=0.014). 37% of patients in the selumetinib group and 0% in the placebo group had an objective response (two-sided p<0.0001). The KRAS mutation codon subtype might impact on prognosis and/or response to therapy. The BATTLE trial suggested that G12V or C KRAS mutations confer relatively poorer outcome within the KRAS mutant NSCLC sub-type (Ihle et al. J Natl Cancer Inst 2012;104:228–39). In cell lines carrying these codons, Akt phosphorylation but not ERK phosphorylation was low compared with other codons, suggesting these codons might confer greater dependence upon MEK/ERK signaling. We sought to understand if any codons or combinations of codons selected for striking treatment effects either between or within treatment groups in the Phase II study.

      Methods
      Post-hoc analysis explored the hypotheses that patients whose tumours carried G12C or G12V KRAS mutations would have a worse prognosis and that these patients would have a better outcome with the addition of selumetinib. Clinical benefit was measured by PFS, OS and ORR.

      Results
      G12V or G12C mutations were present in 57% of patients and whilst not reaching statistical significance, trends for PFS, OS and ORR support the hypothesis (see table, PFS). Patients with G12V mutations responded better to selumetinib plus docetaxel than other patients as measured by change in tumour size at week 6 (G12V=-62%, G12C=-8%, G12D=+3%, reduction across all codons=-18%; two sided p=0.007). It is therefore possible that trends supporting the primary hypothesis were driven by effects in the small number of G12V codons (n=9). Table. Summary of analysis of progression-free survival (PFS): MITT by mutation subgroup

      Subgroup Selumetinib + docetaxel, n (number of PFS events) Docetaxel, n (number of PFS events) Selumetinib + docetaxel vs docetaxel, PFS HR (80% CI)
      G12C or G12V 24 (18) 23 (21) 0.48 (0.31–0.74)
      Other 19 (17) 17 (15) 0.72 (0.44–1.16)
      Overall 43 (35) 40 (36) 0.58 (0.42–0.79)

      Conclusion
      Any impacts of codon sub-type on the treatment effect in this trial were not sufficiently significant to be detected in this small Phase II trial of 87 patients, but the trends observed in this retrospective subgroup analysis warrant monitoring of the impact of specific codons or groups of codons in future clinical trials.

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    O16 - NSCLC - Targeted Therapies III (ID 115)

    • Event: WCLC 2013
    • Type: Oral Abstract Session
    • Track: Medical Oncology
    • Presentations: 1
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      O16.02 - Efficacy of standard care for second-line advanced non-small cell lung cancer (NSCLC) by <em>KRAS</em> mutation status: observations on MEK inhibitor enhancement of chemotherapy (ID 3329)

      10:30 - 12:00  |  Author(s): I. Smith

      • Abstract
      • Presentation
      • Slides

      Background
      KRAS mutations that activate the MEK/ERK pathway are found in 20–30% of NSCLC. Response to second-line therapies for advanced NSCLC may be different in the presence or absence of a KRAS mutation. MEK inhibitors are being developed in combination with cytotoxic chemotherapy for NSCLC, based on preclinical findings that MEK inhibition increases pro-apoptotic BIM levels, enhancing cytotoxic therapy, and that MEK inhibition reduces KRAS mutation-induced oncogenic drive. We reviewed available information from KRAS mutation-positive (KRAS+) and KRAS wild-type subsets in AstraZeneca clinical studies in second-line NSCLC and published data on MEK inhibitors. Our objective was to determine whether differential therapeutic activity is present in KRAS+ and KRAS wild-type populations and whether preclinical findings translate into enhanced tumour response.

      Methods
      We reviewed data on objective clinical response in second-line NSCLC according to KRAS status in five randomised double-blind Phase II or III studies of gefitinib, vandetanib or selumetinib and three published studies of trametinib. Ninety-five percent confidence intervals (CI) around point estimates of objective response were calculated using exact (Clopper-Pearson) methods for a single proportion.

      Results
      The studies involved 4466 patients receiving second- or later line treatment for advanced NSCLC. In total, 1286 patients received singlet chemotherapy (docetaxel or pemetrexed), including 429 with known tumour KRAS mutation status: 138 had KRAS+ and 291 had KRAS wild-type NSCLC. Additionally, 132 patients with known KRAS status received singlet chemotherapy plus a MEK inhibitor (selumetinib or trametinib): 91 with KRAS+ and 41 with KRAS wild-type NSCLC. Figure 1

      Conclusion
      Our retrospective comparison suggests that second-line singlet chemotherapy response rates may be greater in KRAS wild-type than in KRAS+ NSCLC, and that MEK inhibition may enhance second-line chemotherapy activity in both KRAS+ and KRAS wild-type NSCLC. These observations support prospective validation of these results and further evaluation of MEK inhibitors plus chemotherapy in second-line KRAS unselected NSCLC.

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    P3.11 - Poster Session 3 - NSCLC Novel Therapies (ID 211)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Medical Oncology
    • Presentations: 2
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      P3.11-028 - Exploration of the relationship between neutrophil count and clinical consequences in patients with advanced non-small cell lung cancer (NSCLC) receiving selumetinib plus docetaxel: predicted effect of primary prophylactic GCSF (ID 2320)

      09:30 - 16:30  |  Author(s): I. Smith

      • Abstract

      Background
      Selumetinib (AZD6244, ARRY-142886) is an orally available, potent and selective, non-ATP-competitive MEK1/2 inhibitor being investigated with docetaxel for treatment of KRAS mutation-positive advanced NSCLC. A randomised Phase II study of selumetinib 75 mg twice daily (bid) plus docetaxel 75 mg/m[2] q21d (SEL-DOC 75/75), with secondary granulocyte colony-stimulating factor (GCSF) prophylaxis if indicated, has shown promising efficacy in this setting but with more diarrhoea, neutropenic events, infections, hospitalisations and dose modifications than docetaxel alone (Jänne et al. Lancet Oncol 2013;14:38–47; NCT00890825). Data from a small number of patients with advanced solid tumours in an open-label, Phase I study (NCT00600496) suggested that primary prophylactic (pp) GCSF reduces the incidence of neutropenic events associated with SEL-DOC 75/75 (Kim et al. Mol Cancer Ther 2011;10[Suppl 1:B225). We evaluated whether pp-GCSF could influence the incidence of hospitalisation or infection during treatment with SEL-DOC 75/75 using bias-reduced logistic regression modelling and medical review of data from NCT00890825.

      Methods
      Neutrophil counts and events of hospitalisation or infection from the safety analysis set of study NCT00890825 were used for modelling. This included 86 patients with KRAS mutation-positive advanced NSCLC randomised to receive second-line treatment with SEL-DOC 75/75 or placebo bid plus docetaxel. The relationship between maximum reduction in absolute neutrophil count (mr-ANC) and infection or hospitalisation events was explored using bias-reduced logistic regression (Firth. Biometrika 1993;80:27–38; Kosmidis. brglm, v0.5-6: www.ucl.ac.uk/~ucakiko/software.html). Starting models included terms for treatment group, mr-ANC, interaction between treatment group and mr-ANC, and baseline ANC. The final fitted models were used to predict the proportion of patients with events across the range of mr-ANC. Reported reasons for hospitalisation, dose modification and treatment discontinuation were medically reviewed in the context of expected pp-GCSF effect.

      Results
      The fitted logistic regression model showed some evidence of a relationship between hospitalisation events and mr-ANC for both treatment groups. A zero mr-ANC (assumed effect of pp-GCSF) predicted hospitalisation in 30% of patients (80% prediction interval 18–44%) in the SEL-DOC 75/75 group and 10% (5–18%) in the placebo plus docetaxel group. The observed incidence of hospitalisations in study NCT00890825 was 48% (80% confidence interval [CI] 37–58%) and 19% (11–29%) of patients, respectively. There was limited evidence of a relationship between events of infection and mr-ANC, suggesting other factors (eg immunosuppression and altered integrity of gastrointestinal wall) may influence the incidence of infection reported with this combination. Medical review indicated that use of pp-GCSF could reduce hospitalisation incidence during SEL-DOC 75/75 from observed 48% to a point estimate of 34% (80% CI 25–45%), and dose modification due to febrile neutropenia or infection from 23% to 5% (80% CI 1–12%). Permanent discontinuation of SEL-DOC 75/75 for reasons other than disease progression did not appear to be affected by pp-GCSF use.

      Conclusion
      Prevention of ANC reduction is predicted to lower the incidence of hospitalisation events in patients receiving treatment with selumetinib plus docetaxel for NSCLC. These findings support pp-GCSF use to reduce the incidence of hospitalisations previously reported with the SEL-DOC 75/75 regimen.

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      P3.11-029 - The SELECT-1 study design: selumetinib in combination with docetaxel for second-line treatment of <em>KRAS</em> mutation-positive locally advanced or metastatic non-small cell lung cancer (ID 2231)

      09:30 - 16:30  |  Author(s): I. Smith

      • Abstract

      Background
      KRAS mutations are the most common mutation type in patients with non-small cell lung cancer (NSCLC) with adenocarcinoma histology (Califano et al. Drugs 2012;72[Suppl 1:]28–36). The presence of the KRAS mutation has been associated with a poor prognosis (Mascaux et al. Br J Cancer 2005;92:131–139) and a therapy targeting Ras has yet to be proven in clinical trials. Selumetinib (AZD6244, ARRY-142886) is an orally available, potent and selective, non-ATP-competitive MEK1/2 inhibitor. MEK1/2 are proteins downstream of Ras in the Ras/Raf/MEK/ERK pathway. It is anticipated that inhibition of MEK activity should inhibit transduction of the mitogenic and survival signals via this pathway, resulting in an inhibition of tumour proliferation, differentiation and survival. A randomised Phase II study evaluating docetaxel plus selumetinib or placebo in pretreated patients with KRAS mutation-positive advanced NSCLC has previously demonstrated a significant improvement in terms of response rate, progression-free survival (PFS) and patient-reported outcomes (PROs) in favour of the combination arm (Jänne et al. Lancet Oncol 2013;14:38–47).

      Methods
      The SELECT-1 study is a randomised, double-blind, placebo-controlled Phase III study that will assess the efficacy and safety of selumetinib in combination with docetaxel in patients receiving second-line treatment for KRAS mutation-positive locally advanced or metastatic NSCLC (Stage IIIB–IV). Eligible patients will have centrally confirmed KRAS mutation-positive locally advanced or metastatic NSCLC, be suitable for second-line treatment and have had no prior treatment with docetaxel or a MEK inhibitor. Patients must have measurable disease, histologically or cytologically confirmed locally advanced or metastatic NSCLC and a WHO performance status (PS) of 0–1. Patients will be randomised in a ratio of 1:1 to receive selumetinib (75 mg, orally twice daily [BID]) or matching placebo BID in combination with docetaxel (intravenously 75 mg/m[2], on Day 1 of every 21-day cycle) until objective disease progression, intolerable toxicity or occurrence of another discontinuation criterion. Approximately 4000 patients will need to be screened from 220 centres globally to identify 634 KRAS mutation-positive patients for the study. Patients will be stratified at randomisation based on their WHO PS (1/0) and tumour histology (squamous/non-squamous). Following randomisation, patients will attend for visits on Day 8, 15, 22, 43 and every 3 weeks thereafter for as long as they are receiving study treatment. Tumour evaluation according to Response Evaluation Criteria in Solid Tumors version 1.1 guidelines will be performed at screening, Week 6, Week 12 and every 6 weeks thereafter, relative to the date of randomisation. The primary study endpoint is PFS; secondary endpoints include overall survival and objective response rate. Efficacy data will be analysed on an intent-to-treat basis using randomised treatment. Blood samples will be taken to assess the pharmacokinetics of selumetinib. The study will also evaluate PROs and safety for the selumetinib/docetaxel combination compared with placebo/docetaxel. In addition, outcome based on KRAS mutation type will be assessed.

      Results
      Not applicable.

      Conclusion
      This Phase III study will confirm the efficacy of selumetinib in combination with docetaxel in patients with NSCLCs that harbour mutations of KRAS and who are eligible for second-line treatment.